BANNING OF NIMESULIDE IN VETERINARY USE IN INDIA  AS IT IS TOXIC TO VULTURES 

BANNING OF NIMESULIDE IN VETERINARY USE IN INDIA  AS IT IS TOXIC TO VULTURES 

India has become a dumping ground for banned drug, also the business for production of banned drug is booming. All the formulations are meant for prevention or treatment of ailments and diseases, out of which only a few drugs are lifesaving and essential, rest of the drugs are substitutes of each other. Banned drugs are still available in developing countries like India due to lack of law enforcement physician awareness and the drug control authorizes fails to inform all the hospital of the status of medicine. Some of the dangerous drugs have been globally discarded but are available in India. The most common are like Nimesulide, Furazolidone, Phenylpropanolamine and other over the counter preparation are banned by USFDA due to their side effect on kidney, liver and nerve. Unfortunately analgesic, antidiarrheal and cough preparations which are banned in other countries and are blindly used in India as over the counter drugs because of unawareness, lack of law enforcement and corruption. The Government of India is in the process of developing a regulatory regime designed to ensure the quality, safety and performance of medical devices. The pharmacist should take interest in public information campaigns and educate consumers and thus can play an important role of eliminating the banned drugs from market.

A drug is “a chemical or synthetic substance used in the, cure, prevention or diagnosis of disease or used to otherwise enhance physical or mental well being.

“PILL FOR EVERY ILL” is a saying which is being focused and pursued. It may not be possible to have a disease free world but we can aspire for solutions to relieve misery and make patient’s life more comfortable to a greater extent. The main aim is to ensure good quality of life to patients. This can only be achieved with quality drugs with maximum therapeutic benefit and minimum side effects, available to all at low cost. Apatient relies on his physician and prescriber for his treatment. Thus it is the duty of the physician to meet the patient’s requirements to their satisfaction. A drug is usually prescribed to a patient for its positive effect but may give rise to several adverse effects. Some of the common ones that are easily available and used frequently without doctor’s prescription are Phenyl propanolamine, analgin, 1, 2 cisapride and nimesulide among several others which, 3 continue to be sold as OTC in India . Coxibs were the widely prescribed drugs until the recent setback with rofecoxib, which was withdrawn from the market by the innovator due to increased risk of heart attacks andstrokes observed with its long-term use . Analgin was widely used, easily available, relatively cheap and efficacious analgesic. Initially this drug was banned in 1974 because of the myelotoxicity but significant methodological flaws in the study led to criticism and the drug was unbanned in 1995 but as a prescription drug only. Further studies led to more controversies regarding its association with agranulocytosis and it was again 6 withdrawn from the market in 1999. It was estimated that the fatal agranulocytosis occurred in one out of 10,000 users of the drug analgin. Other serious toxic effects like life threatening exfoliative dermatitis, toxic epidermal necrolysis and renal papillary necrosis causing death in 7 17 to 93% cases . These are used as pain-killers but latest research shows that long term use of such medicines can affect human health in various ways by damaging liver, causing irregular heartbeats, depression, and blood pressure 8 fluctuations etc . This is the prime reason that most of European countries have disqualified and banned the manufacturing and consumption of these drugs. Numerous studies have shown life threatening ADRs with nimesulide such as hepatotoxicity, renal toxicity severe skin reactions, GI toxicity, and coronary artery 9. insufficiency Pediatric nimesulide was withdrawn from the Indian market because of the potential hazards of the drug. . Therefore the manufacturing, sale, distribution and marketing of these drugs need to be outlawed, such drugs are termed as banned drugs. More than 60,000 branded formulations are available in India. One of the latest threats facing the global pharmaceutical industry and healthcare is the presence of spurious/substandard drugs in the market. This definition of counterfeit includes not only completely fake drugs but also those that have been tampered with, adulterated, diluted, repackaged, or relabeled so as to misrepresent the dosage, origin, or expiration date, as well as those substandard drugs that are cheaply produced in order to make unlawful profits.

PROCESS OF BANNING

When a serious problem occurs in health care there is always a “knee-jerk” response by many to impose a ban and thus provide an immediate and definitive response to the issue. While such responses may be emotionally satisfying they often represent answers which are “smarter than we are” and may end up causing more harm than good. The classic example of drug banning has been the saga of thalidomide. Thalidomide, developed in Germany in the mid-1950’s, became popular on a world-wide basis as a tranquilizer and sleep inducing medication. Thalidomide initially appeared to be safe. The fact was that it was a teratogen (capable of birth defects) associated with maldevelopment of fetal extremities. Incidentally, there is no common regulation available till date forcing banning of drugs simultaneously in all countries. The Drug Technical Advisory Board (DTAB) in India is the final authority on imposing a ban. An executive committee examines the harmful effects of the drugs and reports the results to the DTAB. If any drug is found to have harmful side-effects, the Government issues the ban order and all manufacturers and wholesalers are asked not to stock the particular medicine. The DCGI notifies all state drug authorities, pharmacists associations and manufacturers about the ban of the drug. Authorities are instructed to carry out inspections. Licenses of pharmacists stocking banned drugs can be revoked under 30 the Drug and Cosmetics Act. Officials at the Drug Controller of India (DCGI) office, however, had a different take on the issue of banned drugs. “Screening of irrational or harmful drugs is an ongoing exercise and over 79 categories of formulations have been banned so far. With a view to ensuring proper dispensing and rational use of drugs, packing has been standardized. Even after a drug gets market approval, safety and efficacy is continuously examined on the basis of information received through pharmaco-vigilance, post-marketing surveillance and information received from other countries.

Banned Drugs– banned drugs are drugs that not allowed to intake because they could artificially improve their performance and shows various adverse effects more than therapeutic effects. Whose production or use is prohibited or strictly controlled via prescription.“Drug Controller general of India” is the highest authority in India to expand the approval of any drug or to ban a drug. Some of the dangerous drugs have been globally discarded but are available in India.The most common are like Nimesulide,Phenylpropanolamine,Furazolidone, etc.

Reason For Banning a Drug -Drugs undergo rigorous testing before they are introduced into the market. The efficacy as well as safety profiles of the drug are tested. In spite of this, some adverse effects of drugs appear only after the drug is released called Pharmacovigilance.Pharmacovigilance is the Pharmacological science relating to the detection, assessment understanding and prevention of adverse effects, particularly, long-term and short-term side-effects of medicines.“Drug Controller general of India” is the highest authority in India to expand the approval of any drug or to ban a drug. If any is to have harmful side-effects, the government issues the ban order and all manufacturer and wholesaler are asked not to stock the particular medicine.“If doctors stop prescribing drugs that are harmful to patients”health, chemists will automatically stop selling since there are no patients asking for it, and hence, manufacturers do not produce it. Certainly, much of the problem can be solved like that, ‘the manufacturers have every reason to sell their products if there are buyers.”

WHY INDIA STILL SELLING BANNED DRUGS

India has become a dumping ground for banned drugs.The irony is that very few people know about the banned drugs and consume them unaware, causing a lot of damage of themselves. The issue is severe and we must not delay in spreading the warning message to the offenders and innocent people.

MOST OF THE DRUGS BANNED IN OTHER COUNTRIES BUT AVAILABLE IN INDIA

Oxyphenbutazon– Oxyphenbutazone, a metabolite of phenylbutazone,is an NSAID. It has been used for episceleritis, osteoarthritis,and rheumatoid arthritis etc. the severe adverse effects of oxyphenbutazone, which give rise to further complications include allergic reactions, abdominal pain, blurred vision. Metamizole: Metamizole (Dipyrone) belongs to a group of drugs that eliminate pain and reduce fever. Metamizole can cause damage to the bone marrow (granulocytopenia, agranulocytosis, hemolytic anemia, aplastic anemia.) ,digestive disorders etc.

Cisapride– Cisapride is a “Prokinetic Agent” that used for treatment of gastroesophageal reflux disease (GERD). There is no evidence it is effective for this use in children. evidence for its use in constipation is not clear. It has been found to cause cardiac arrhythmias (irregular heart rhythms)

Nimesulide- Nimesulide is a non-steroidal anti-inflammatory drug, used for painful inflammatory conditions, back pain, dysmenorrheal, postoperative pain, osteoarthritis and fever. Caution should be exercised in patients with history of stomach problem, high blood pressure, fluid retention, abdominal discomfort, heartburn, abdominal cramps, nausea, vomiting and diarrhea, headache, dizziness and drowsiness, blood in urine and kidney failure.

Phenylpropanolamine– Phenylpropanolamine is a “Prokinetic Agent” that used for treatment of gastroesophageal reflux disease (GERD). But heart stroke and heart attack can cause due to adverse effect of phenylpropanolamine.

Quiniodochlor- Quiniodochlor is a antibacterial agent, used for dermatophytosis, mycosis barbae, seborrhoeic dermatitis, infected eczema, furunculosis, and pityriasisi veriscolor. It caused to nausea, transient loose and green stools, itching and goiter.

Cerivastanin– Cericastatin prevents the risk of stroke and heart attack .it functions by blocking away the enzymes in the liver that is responsible in the production of cholesterol inside the body. There are several side effects associated by using Cerivastatin, for example- diarrhea, nasal congestion, constipation, headache and heartburn, muscle damage, sexual problems, fever, difficulty in breathing etc.

Droperidol– Droperidol is an Antidopaminergic drug used as an antiemetic and antipsychotic. It also often used for neuroleptanalgesic anesthesia and sedation in intensive care treatment. but it causes dysphoria, sedation, hypotension resulting from peripheral alpha adrenoceptor blockade, prolongation of qt interval which can lead to extra pyramidal side effects such as dystonic reaction.

Furazolidone-Furazolidone is a Nitrofuran Antibacterial. It is marketed under the brand name furoxone. furazolidon has been used in human and veterinary medicine. in humans it has used to treat diarrhea and enteritis caused by bacteria or protozoan infections. it has been used to treat cholera and bacteremic salmonellosis, and helicobacter pylori infections. it has many side effects, and as with other nitro furans generally, minimum inhibitory concentrations also produce systemic toxicity (tremors, convulsions, peripheral neuritis, gastrointestinal disturbance, depressions of spermatogenesis.)

Nitrofurazone- Nitrofurazone is bactericidal for most pathogens that commonly cause surface skin infections.Topical nitrofurazone is indicated as an adjunctive therapy second and third degree burns. The adverse effects have been selected on the basis of their potential clinical significances are itching, rash and swelling.

Thioridazine- Thioridazine is an antipsychotic medicine called a phenothiazine. It is used to treat schizophrenia. But it can cause a life-threatening heart rhythm disorder, uncontrollable muscle movements of your lips, tongue, eyes, face, arms or legs.

Pergolide– Pergolide is a drug normally used for the treatment of parkinson’s disease. But cardiovascular system can damaged as the adverse effect of pergolide.

Piperazine- Piperazine was introduced to medicine as a solvent for uric acid. PIPERAZINE was first introduced as an anthelmintic. piperazine is used in the treatment of worm infections. following side effects can causes the human body: blurring of vision, clumsiness, crawling or tingling feeling of the skin, fever, irregular, twisting movement, especially of the face, arms and legs, joint pains, and itching or skin rash etc.

Phenolphthalein– Phenolphthalein is a astringent normally used as a laxative. The several adverse effects of phenolphthalein are heart stroke and heart attack etc.

Tegaserod- Tegaserod is a medicine used to treat severe, chronic, irritable bowel syndrome (IBS) in women who have constipation (and not diarrhea) as their main bowel problem. But it causes to new or worsening stomach pain, blood in stools, ongoing diarrhea, severestomach pain or cramps, headache, dizziness, or migraine, back pain or joint etc.

Analgin-Analgin is a medicine of pyrazolone group possessing hard analgesic and antipyretic effects and moderate anti-inflammatory activity and used for the treatment of pains of different origin and variable intensity: toothache, headache, arthralgia, myositis, mild to moderate visceral pain, high fever. After prolong administration very rarely can be observed agranulocytosis, leucopenia, and thrombocytopenia, proteinuria, interstitial nephritis. In sensitive patients rashes, urticaria, quincke’s edema, asthmatic attacks, and very rarely anaphylactic shock are possible.

REGULATIONS & GUIDELINES

Process of banning drug in India is done by DTAB (Drug technical advisory board) which is the final authority on imposing a ban. Drug controller general of India notifies all state drug authorities and manufacturer about ban on the drug. At IPA we understand the problems faced by pharma professionals in accessing requisite information in order to comply withthe regulatory requirements At home and in the regulated foreign markets. We’ve tried to simplify things for you by assembling the important Indian and international guidelines and regulations in this section.

REASONS OF AVAILABILITY OF BANNED DRUGS IN INDIA

* A lengthy legal procedure to ban any drug in India which is banned in developed countries gives long time to manufacturers to manufacture these banned drugs in India. Commercial interests of pharmaceutical companies, corruption, lack of transparency and accountability is the major reason for such delay in 28 banning procedure. * Regulatory bodies lack enforcement power. * Due to the poverty line in India these drugs are easily marketed at low costs. * Many private practitioners and physicians are unaware about the ban. * Non –compliance by the patient by self prescribing the drugs for common ailments and disorders. The patient has a mindset that he gets well fast with the drug he takes like Nimesulide, Rofecoxib, Phenylpropanolamine for common ailments such as cold, cough, head ache, etc and they don’t know about the side effects, whether these . 29,30 drugs are banned or not * Because of self prescription, numbers of allergic and anaphylactic reactions are occurring frequently in India. This can be prevented by public awareness programmes regarding the status, use, and side effects of self prescription. * Non-availability of appropriate drugs and their high 28, 29 cost . 29,30 * Prescribers lack of knowledge and experience * In some places such as Ludhiana, the department has no provision for notifying to hospital and doctors about the status of these banned drugs except through newspaper. * One of the reasons for the free availability of banned drugs in the market is this communication gap between the DCGI and state drug controllers. A recent case concern phenformin formulations. The product is still available in the market after its ban order issued on st 1 October 2003. A serious problem confronting the medical profession today is the lack of updating of their knowledge about existing and new drugs. * Drug Inspectors cannot reach out & inspect every pharmacist/wholesaler because Drug Inspectors are too few. The list of drugs prohibited for manufacture and sale

SUGGESTIONS

There are various suggestions, which when taken into consideration can play an important role in reducing the marketing of banned drugs in INDIA. * All new molecules and products have to be approved by the Drugs Controller General, India (DCGI). Once a new molecule is licensed, the state drugcontrollers take over and monitor pharmaceutical manufacturing facilities located in their own jurisdictions. * Government should amend the law periodically with the consent of regulatory bodies of other developed countries. The list of banned drugs should be clearly justified to the target professionals such as pharmacist, 32 physician, manufacturer, etc . * Promotion of unsafe drugs in the developing world has long attracted criticism, particularly when products have been banned or restricted in the country of manufacture. Pharmaceutical adverts, labeling, and package inserts in developing countries often show the twin problems of exaggerated indications and minimized adverse effects. Government should look after critical issues such as drug promotion, labeling regulation of the OTC drugs, marketing of irrational FDC and banned 33 drugs, etc . Unfortunately we have not yet learned that the banning of therapeutic agents/ drugs is not warranted. The banning of the non-steroidal anti-inflammatory drug Rofecoxib is a more recent example of this. Warranting is clear identification of the known risk and communication of this fact to patient, so that they provide accurate information allowing true informed consent, such informed consents are more safe than banning. This safeguard is, however, only meaningful when there are health care consumers placed in the driver’s seat who have the motivation and means to seek out these truths and are also capable of effectively using this information. * There should be an involvement of all categories of

h e a lt h c a r e p r o f e ssi o n a ls i n A D Rs a n d pharmacovigilance planning . ADR reporting should be made mandatory as they are in developed countries.  Pharmacovigilance should be more effective . The aims of such programs are to contribute to the regulatory assessment of benefit, harm, effectiveness, and risk of 16 medicines . They encourage safe rational and effective use of drugs and improve public health. Further they promote understanding, clinical training and effective 3, 36 communication to the public . * More drug information centers should be opened. These centers provide current, independent, unbiased, and critically evaluated drug information that can lead to enhanced quality of patient care, and improved patient outcome. Information provided by such centers helps Prescribers to choose the most appropriate drugs for the patient. They provide ward round participation, provision of drug information, adverse drug reaction monitoring, patient counseling . * Moreover, regulatory authorities, healthcare professionals, researchers and pharmaceutical companies should join hands together to formulate guidelines for the FDC’s to drive away fear from the minds of patients. The pharmacist should educate the masses on how and when to use drugs and provide information to the Prescribers and other health care professionals. It is essential for health care professionals to get acquainted with the list of drugs which are irrational and banned by DCGI. In addition, they should keep themselves updated with the notifications issued by the DCGI to curb irrationalfixed dose combinations. This shall help them to use proper medicines and save patients 37 from unsafe drugs . * Reducing the number of branded drugs facilitates pharmaceutical regulation makes it easier for health care officials to educate consumers about the proper use of 27, 38 available medications in generic form . * The government needs to hold more public information campaigns and community activism to educate the public on the potential dangers of drug use. * The government needs to make sure that the laws made by the regulatory bodies should be enforced and should punish those who distribute such drugs.

Nimesulide  Toxic to Vultures

A paper published in the current issue of Science of the Total Environment (here) confirms that the non-steroidal anti-inflammatory drug (NSAID), nimesulide, is toxic to vultures, following safety testing of the drug on vultures in South Africa.

Since the banning of veterinary diclofenac, the NSAID which drove three species of Gyps vultures to near-extinction in South Asia, there has been an urgent need to test other NSAIDs also available on the market for veterinary use, and which are suspected to also be toxic to vultures. One such drug which is becoming increasingly popular especially in India was nimesulide. The drug was already implicated in the deaths of several vultures in NW India, which showed signs of NSAID poisoning, i.e. visceral gout, coupled with nimesulide residues in the blood (here and here). Now, these published results  confirm that nimesulide is, indeed, highly toxic to vultures.

In a safety testing experiment carried out in South Africa, in which two Cape Griffon Vultures G. coprotheres were given nimesulide, both birds developed increased concentrations of uric acid in the blood and visceral gout, symptoms of kidney failure, and as with diclofenac poisoning, they died within two days of dosing. Double the recommended dose was given to the birds to replicate the common practice in India, where farmers regularly give such large doses of drugs to their injured cattle. Safety testing has been widely conducted to test the toxicity of drugs to birds, and was instrumental in proving the toxicity of diclofenac, which led to its subsequent ban. To avoid too many birds being exposed to a potentially harmful drug, only two birds are given a dose of a drug in the initial phase of the experiment, and if at least one of these birds die then the experiment is stopped and the drug declared toxic. Both birds in this latest experiment were residents of the VulPro Rehabilitation Centre, located outside Pretoria, South Africa, due to injuries that prevented them from ever being released.

Senior Conservation Scientist at the Royal Society for the Protection of Birds (RSPB, Birdlife UK), Dr John Mallord, one of the authors of the recent study, said “The results of this study are incredibly important, confirming what we have suspected for a number of years, that nimesulide can kill vultures”.

Prof. Rhys Green from the University of Cambridge and another co-author added, “The government of India previously acted quickly to ban diclofenac, which prevented vultures from going extinct. Now that we have this evidence of nimesulide’s toxicity, we call upon the Government of India to take urgent steps to ban this drug for veterinary use, to support the ongoing recovery of vulture populations in India and elsewhere in South Asia”.

Bivash Pandav, Director of the Bombay Natural History Society (BirdLife in India) said “India set an important example by banning veterinary diclofenac in 2006, but unless this work prompts similar action for nimesulide, there is a risk that those earlier efforts will have been for nothing. Especially now we know that there are at least two safe alternative drugs available for the vets: meloxicam and tolfenamic acid, there is really no reason to allow such dangerous drugs to be used.

Vinny Naidoo, Dean of Pretoria University and expert veterinary pharmacologist, who led the work said “It is tragic that this work is being driven by conservationists and not by the pharmaceutical industry itself. Hopefully the drug regulators respond quickly, as they did in India for diclofenac as it will save huge numbers of vultures”

This topic was highlighted at the recent annual SAVE meeting, and it was agreed that nimesulide, along with aceclofenac and ketoprofen where the published toxicity evidence is also overwhelmingly clear, and immediate bans of all three veterinary drugs have become the highest single priority for conserving Asia’s vultures.

CONCLUSION

Though each country has its own list of banned drugs, it is worrisome that some drugs that are banned in other countries for proven adverse effects are still available in the Indian market. Some of these drugs are available over – the – counter and people may take it without realizing the risk. A note of caution on these drugs could help patients in deciding whether they want to take the drug. Please make sure that patients buy drugs only if prescribed by a doctor. And that also from A reputed drug store. Not many people know about these banned drugs and consume them causing a lot of damage to themselves. For illegal drugs that are not diverted prescription controlled substances, some critics believe that illegal recreational use is inherently irresponsible; due to the unpredictable and unmonitored strength and purity of drugs are the risks of addiction, infection, and other side effects.The Central Drugs Standard Control Organisation run by the government of india has to made a strict guidelines over the list of drugs have been banned by European union and USA.

In conclusion one can say that, though several drugs are banned or restricted for sale in the developed countries such as USA these banned drugs are still being sold in developing countries such as India. Therefore it becomes important for the government to implement laws, strict on manufacturers, wholesalers and retailers’. There should be creation of awareness amongst physicians, health professionals and general public about the ADR of these drugs. If all these steps are taken in a well defined and unified way the market for these banned drugs can be eliminated permanently and rapidly.

Compiled  & Shared by- This paper is a compilation of groupwork provided by the Team, LITD (Livestock Institute of Training & Development)

 Image-Courtesy-Google

 Reference-On Request

List of banned medicines in India

LIST OF DRUGS PROHIBITED FOR MANUFACTURE AND SALE THROUGH INDIA

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